Ozone is the principle oxidant air pollutant contaminating the atmosphere of most American cities. The pathobiologic response of the mammalian respiratory system to inhalation of ambient concentrations of ozone focuses on the epithelium, varies by species, varies by position within the airway tree and changes in nature with duration of exposure. The premise behind which this Program Project is organized is that continued exposure to ozone and other oxidant pollutants fundamentally alters the biological homeostasis of the respiratory system. Two projects are oriented towards defining the role of inflammatory cells, especially the neutrophil, in facilitating repair and establishing an altered steady state and the neurologic mechanisms by which ozone alters airways type of reactivity. The other two projects focus on defining the basic mechanisms by which; the altered respiratory system interacts with environmental toxicants which require metabolism via the cytochrome P-450 monooxygenase system, and the altered pathobiology created by the interaction of ozone with another oxidant air pollutant, nitrogen dioxide, in altering the pathologic response and the interaction between the respiratory epithelium and the extracellular matrix. This Program Project is a multidisciplinary, highly interactive research program which will utilize cellular biological, pathobiological, biochemical and molecular approaches to defining fundamental mechanisms of ozone injury and repair in the respiratory system. The Program will define these mechanisms in sensitive (Rhesus monkey) and less sensitive species (rat, guinea pig), to identify critical parameters which serve as a basis for making predictions of long-term consequences of photochemical smog on humans. Utilizing species of variable sensitivity and variable respiratory anatomical organization with similarities and differences to humans will ensure more confident extrapolation.